Implantable system with drug-eluting cells for on-demand...

Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Arterial prosthesis – Drug delivery

Reexamination Certificate

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C604S891100

Reexamination Certificate

active

06824561

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to implantable systems that include medical devices (e.g., stents, vascular grafts, stent grafts) that function as a carrier for eukaryotic cells (e.g., genetically engineered endothelial cells). Such cells are capable of producing and releasing a therapeutic agent (e.g., tissue-type Plasminogen Activator) for on-demand localized treatment of conditions such as coronary artery disease. The cells or the device carrying them release the therapeutic agent upon the application of a stimulus (e.g., electrical stimulus).
BACKGROUND OF THE INVENTION
Coronary Artery Disease (CAD) affects 1.5 million people in the USA annually. About 10% of these patients die within the first year and the rest suffer from myocardial infarction and develop related symptoms, such as arrhythmias, CHF, and mechanical complications (e.g., aneursym, thrombus formation, pericarditis). During CAD, formation of plaques under the endothelial tissue narrows the lumen of the coronary artery and increases its resistance to blood flow, thereby reducing the O
2
supply. Injury to the myocardium (i.e., the middle and thickest layer of the heart wall, composed of cardiac muscle) fed by the coronary artery begins to become irreversible within 0.5-1.5 hours and is complete after 6-12 hours, resulting in a condition called myocardial infarction. If the ischemia due to stenosis of the coronary artery lumen could be reduced by increasing the blood circulation to the myocardium, the major cause of most of the heart disease would be eliminated.
Current and proposed treatments for coronary artery disease typically focus on pharmacological approaches and surgical intervention. For example, angioplasty, with and without stents, is a well known technique for reducing stenosis. Systemically administered drugs (e.g., anticoagulants) are also commonly used, however, such drugs become diluted, which can reduce their potency by the time they reach the remote site. Furthermore, systemic administration can be deleterious because it can lead to complications as a result of the high dosages required upon administration to allow for dilution that occurs during transport to the remote site. Therefore, localized delivery of therapeutic agents is preferred. Local delivery is advantageous in that the effective local concentration of delivered drug is much higher than can normally be achieved by systemic administration.
Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral vessels. Stent designs include those of U.S. Pat. Nos. 4,733,655 (Palmaz), 4,800,882 (Gianturco), or 4,886,062 (Wiktor). Such designs include both metal and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents are also used to deliver a drug (e.g., antiplatelet agents, anticoagulant agents, antimicrobial agents, antimetabolic agents) at the site of contact with the vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz) and in International Patent Application Nos. WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), for example. Anticoagulant substances such as heparin and thrombolytic agents have also been incorporated into a stent, as disclosed, for example, in U.S. Pat. Nos. 5,419,760 (Narciso, Jr.) and U.S. Pat. No. 5,429,634 (Narciso, Jr.). Stents have also been used to deliver viruses to the wall of a lumen for gene delivery, as disclosed in U.S. patent application Ser. No. 08/746,404, filed Nov. 8, 1996 (Donovan et al.).
Stents seeded with autologous endothelial cells (Dichek, et al.,
Circulation
, 80, 1347-1353 (1989)) are disclosed as a method for delivering recombinant protein over time to the vascular wall. The concentration of secreted protein produced by the endothelial cells that is required to treat the surrounding vascular tissue can be significantly higher than could be tolerated if delivered systemically. However, in order to be effective, it is not only necessary to release a high dose of the drug, but it is also necessary to achieve controlled release, e.g., immediately after an occlusion. Thus, it would be desirable to control the release of such cellular components into the surrounding tissue when needed (i.e., on demand). The present invention provides such a system.
Many of the following lists of patents and nonpatent documents disclose information related to the local delivery of therapeutic agents using medical devices, such as stents. Others are directed toward stent designs and other medical devices as well as genetically engineered cells, for example.
TABLE 1a
Patents
Patent No.
Inventor(s)
3,523,807
Gerendas
4,476,868
Thompson
4,540,573
Neurath et al.
4,548,736
Muller et al.
4,556,063
Thompson et al.
4,733,655
Palmaz
4,800,882
Gianturco
4,821,723
Baker et al.
4,886,062
Wiktor
4,944,659
Labbe et al.
5,102,417
Palmaz
5,131,388
Pless
5,144,949
Olson
5,158,078
Bennett et al.
5,192,297
Hull
5,199,428
Obel et al.
5,207,218
Carpentier et al.
5,312,453
Shelton et al.
5,314,430
Bardy
5,330,507
Schwartz
5,354,316
Keimel
5,372,600
Beyer et al.
5,409,009
Olson
5,419,760
Narciso, Jr.
5,429,634
Narciso, Jr.
5,510,077
Dinh et al.
5,545,186
Olson et al.
5,674,722
Mulligan et al.
5,702,427
Ecker et al.
U.S. Pat. Appl.
Donovan et al.
08/746,404, filed
Nov. 8, 1996
TABLE 1b
Foreign Patent Documents
Document No.
Applicant
Publication Date
WO 90/13332
Cedars-Sanai Medical Ctr.
Nov. 15, 1990
WO 91/12779
Medtronic, Inc.
Sep. 5, 1991
WO 96/28841
Smela et al.
Sep. 19, 1996
WO 96/34417
Smela et al.
Oct. 31, 1996
TABLE 1c
Nonpatent Documents
Bansal et al., “Calcium-Regulated Secretion of Tissue Plasminogen
Activator and Parathyroid Hormone from Human Parathyroid Cells,” J.
Clin. Endocrin. Metab., 74, 266-271 (1992).
“Bioartificial Polymeric Materials Obtained from Blends of Synthetic
Polymers with Fibrin and Collagen”, International Journal of Artificial
Organs, 14(5) (1991).
Blaese et al., “T Lymphocyte-Directed Gene Therapy for ADA SCID:
Initial Trial Results After 4 Years,” Science 270, 475-480 (1995).
Bordignon et al., “Gene Therapy in Peripheral Blood Lymphocytes and
Bone Marrow for ADD Immunodeficient Patients,” Science, 270,
470-475 (1995).
Bouaziz et al., “Effect of constant and modulated electrical charges
applied to the culture material on PGI2 and TXA2 secretion by
endothelial cells,” Biomaterials, 16, 727-734 (1995).
Bouaziz et al., “Vascular endothelial cell responses to different
electrically charged poly(vinylidene fluoride) supports under static and
oscillating flow conditions,” Biomaterials, 18, 107-112 (1997).
Braunwald et al., “Unstable Angina: Diagnosis and Management,”
Clinical Practical Guidelines, No. 10, U.S. Department of Health and
Human Services, Public Health Services, Agency for Health Care Policy
and Research, AHCPR Publication No. 94-0602, 27-92 (1994).
Bugiardini et al., “Relation of Severity of Symptoms to Transient
Myocardial Ischemia and Prognosis in Unstable Angina,” J. Am. Coll.
Cardiol., 25, 597-604 (1995).
Chowdhury et al., “Long-Term Improvement of Hypercholesterolemia
After ex Vivo Gene Therapy in LDLR-Deficient Rabbits,” Science, 254,
1802-1804 (1991).
Dicheck et al., “Enhanced In Vivo Antithrombotic Effects of Endothelial
Cells Expressing Recombinant Plasminogen Activators Transduced With
Retroviral Vectors,” Circulation, 93, 301-309 (1996).
Dicheck et al., “Seeding of Intravascular Stents With Genetically
Engineered Endothelial Cells,” Circulation, 80, 1347-1353 (1989).
Dicheck et al., “Retroviral Vector-mediated Gene Transfer into
Endothelial Cells,” Mol. Biol. Med., 8, 257-266 (1991).
Dunn et al., “Seeding of Vascular Grafts With Genetically Modified
Endothelial Cells,” Circulation, 93, 1439-1446 (1996).
Ekterae et al., “Retroviral vector-mediated transfer and expression of
human tissue plasminogen activator gene in human endothelial and
vascular smooth muscle cells,” J. Vascular Surgery, 21, 953-962 (June
1995).
Fisher et al., “Isolation and Characterization of the Human Tissue-type
Plasminogen Activator S

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